Process for the preparation of optically active cyclohexenones

ABSTRACT

The present invention relates to a process for the preparation of an optically active 5-substituted cyclohexenone (II) by treating an achiral macrocyclic 3-substituted-1,5-diketone (I) in the presence of an optically active sodium, potassium or cesium alkoxide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International applicationPCT/IB2005/000399 filed Feb. 15, 2005, the entire content of which isexpressly incorporated herein by reference thereto.

TECHNICAL FIELD

The present invention relates to the field of organic synthesis and morespecifically to a process for the preparation of an optically active5-substituted cyclohexenone by treating an achiral macrocyclic3-substituted-1,5-diketone in the presence of an optically activesodium, potassium or cesium alkoxide, according to Scheme 1:

BACKGROUND

Optically active cyclohexenone derivatives are useful intermediates orbuilding-blocks for the synthesis of various more complex compounds,such as steroids or macrocyclic ketones.

Despite this fact, to the best of our knowledge, the prior art reportsonly one process to carry out the cyclisation of an achiral di-ketone,in the presence of a chiral promoter, into an optically activecyclohexenone derivative (see C. Agami et al. in Bulletin de la SociétéChimique de France, 1987, 358).

However said method is very specific in both the nature of the chiralpromoter and in the substrate used, and therefore suffers from thedrawback of being of very little versatility.

Indeed, there is disclosed only one possible chiral promoter of thecyclisation, i.e. the amino acid (S)-proline, and only a specific typeof di-ketone, i.e. a 4-alkyl-2,6-heptanedione.

Moreover, the prior art does not provide any suggestion or informationconcerning the possibility to carry out said process with otherpromoters or with other substrates. Concerning the substrate, it is alsouseful to point out that said 4-alkyl-2,6-heptanediones are known to bemore easily activated to perform aldol reactions than, for instance, amacrocyclic 1,5-di-ketone. In fact we have noticed that by applying theprior art experimental conditions to a macrocyclic 1,5-di-ketone thecorresponding optically active cyclohexenone is not obtained.

Therefore, the prior art does not solve the problem of providing aprocess for the preparation of an optically active cyclohexenonestarting from an achiral di-ketone and which is of a more broad scope inthe nature of the starting material and/or in the nature of the chiralcompound used to promote the aldol reaction, i.e. the cyclisation,allowing thus a greater versatility. Moreover, in particular, the priorart does not provide a solution to the problem of providing a processfor the preparation of an optically active cyclohexenone derivativestarting from an achiral macrocyclic di-ketone.

SUMMARY OF THE INVENTION

The present invention now relates about a process for the preparation ofan optically active compound of formula (II) as defined below, startingfrom a substituted 1,5-dione, and using as promoter optically activesodium, potassium or cesium alkoxydes, preferably said alkoxydes areobtained from 1,2-aminoalcohols.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In order to solve the problem above mentioned the present inventionrelates to a process, aimed at the synthesis of an optically activecyclohexenone derivative, in a single step, via an intramolecular aldolcondensation.

Therefore the invention concerns a process for the preparation of acompound of formula

wherein the R¹ represents a linear C₇-C₉ alkanediyl or alkenediyl groupoptionally substituted;R² represents a C₁₋₆ linear, branched or cyclic alkyl or alkenyl groupoptionally substituted or a phenyl group optionally substituted; andthe asterisk means that said compound (II) is in an optically activeform;by treating an achiral di-ketone, the substrate, of formula

wherein R¹ and R² have the meaning indicated in formula (II),in the presence of an optically active sodium, potassium or cesiumalkoxide.

As mentioned above, R¹ and R² can be substituted, for example by up totwo groups. As non-limiting examples, said groups are R or OR groups oreven halogen atoms, wherein R stands for methyl or ethyl. Said R¹ groupmay also comprise a C₃₋₄ acetal group.

According to a preferred embodiment of the invention, R represents aC₁₋₆ linear, branched or cyclic alkyl group.

More preferably, the compound of formula (I) is3-methyl-1,5-cyclopentadecanedione, and therefore the compound offormula (II) is (S)-14-methyl-bicyclo[9.4.0]pentadec-1(11)-en-12-one or(R)-14-methyl-bicyclo[9.4.0]pentadec-1(11)-en-12-one or an opticallyactive mixture of said stereoisomers.

As mentioned above, the invention's process is performed in the presenceof an optically active sodium, potassium or cesium alkoxide.

By “optically active alkoxide” we mean here a compound comprising atleast one moiety having an alkoxy group, i.e. a deprotonated alcoholgroup, and which is optically active. In other words, said opticallyactive alkoxide can be an optically active sodium, potassium or cesiumsalt of a C₄-C₄₀ compound comprising one, two or three of such moietiesor of a carbohydrate, such as a sugar, or of a polymer comprisingoptically active alkoxy groups.

Although it is not possible to provide an exhaustive list of thecurrently known optically active sodium, potassium or cesium alkoxideswhich can be used in the invention's process, the following can be namedas preferred examples:

-   a) a sodium, potassium or cesium salt of a C₄-C₁₈ optically active    mono alcohol, such as a sodium, potassium or cesium salt of an    optically active alcohol of formula

wherein R³ represents a C₁₋₄ alkyl group or an optionally substitutedphenyl group and R⁴ represents a C₁₋₄ alkyl group or a C(R⁵)₂(OR^(4′))group, R⁵ representing a hydrogen atom or a R³ group and R^(4′)representing a C₁₋₆ alkyl group, an optionally substituted phenyl orbenzyl group or a C₃₋₉ trialkyl silyl or a triphenyl silyl group; orsuch as a chiral alcohol of formula R^(3′)—OH, wherein R^(3′) representsa C₇₋₁₂ chiral hydrocarbon group;

-   b) a sodium, potassium or cesium salt of    -   a C₃-C₁₈ optically active 1,2-diol, such as a sodium, potassium        or cesium salt of an optically active diol of formula

wherein each R⁶ represents an optionally substituted phenyl group, aC₁₋₆ alkyl group or a COOR⁷ group, R⁷ representing a C₁₋₄ alkyl group;

-   -   a C₄-C₁₈ optically active 1,3-diol, such as a sodium, potassium        or cesium salt of an optically active diol of formula

wherein each R⁶ has the meaning indicated above;

-   -   a C₅-C₃₅ optically active 1,4-diol, such as a sodium, potassium        or cesium salt of an optically active diol containing a moiety        of formula

or such as a sodium, potassium or cesium salt of an optically activediol of formula

wherein R⁵ has the meaning indicated above;

-   c) a sodium, potassium or cesium salt of a C₄-C₂₅ optically active    alcohol containing a nitrogen in the β position, such as a sodium,    potassium or cesium salt of an optically active 1,2-amino-alcohol of    formula

wherein R³ has the meaning indicated above, R^(7′) represents a R⁴ or R⁵group as defined above and R⁸ represents an optionally substitutedphenyl group or a C₁₋₉ alkyl or alkylbenzene group and R^(8′) representsa R⁸ group or a SO₂R³, R³CO, CH₂CH₂NR³ ₂, SiR³ ₃, PO(OR³)₂ group;optionally R³ and R^(7′) can be bonded together to form a C₅₋₁₀ ring orR^(7′) and R⁸ can be bonded together to form a C₄₋₅ heterocycle, or R⁸and R^(8′) can be bonded together to form a C₂₋₅ heterocycle;

or such as a sodium, potassium or cesium salt of an optically activeiminoalcohol of formula

wherein each R³, R⁵ and R^(7′) have the meaning indicated above;

-   d) a sodium, potassium or cesium salt of a C₁₅₋₃₈ compound having    two or three groups derived from an optically active alkoxide    mentioned under a), b) or c); or-   e) a sodium, potassium or cesium salt of an optically active    alkoxide mentioned under d) and which is supported on an insoluble    material such as silica, Merrifield resins, gold or polystyrenes.

Examples of substituents of phenyl groups are Cl, F, Br, R′, SR′, SO₂R′,SOR′, NO₂, NR′₂ or OR′ groups, wherein R′ stands for a C₁₋₄ alkyl group.Said aromatic rings can be substituted by one or two of said groups.

According to a particular embodiment of the invention, said opticallyactive sodium, potassium or cesium alkoxide comprises one or two alkoxygroups and is:

-   a) a sodium, potassium or cesium salt of an optically active alcohol    of formula

wherein R⁹ represents a C₁₋₄ alkyl group or an optionally substitutedphenyl or benzyl group and R¹⁰ represents a phenyl group optionallysubstituted by one C₁₋₄ alkyl group;

-   b) a sodium, potassium or cesium salt of an optically active    1,2-diol of formula

wherein each R¹⁰ has the meaning indicated above;

or a sodium, potassium or cesium salt of an optically active 1,4-diol offormula

wherein each R¹¹ represents a C₁₋₄ group or an hydrogen atom;

-   c) a sodium, potassium or cesium salt of an optically active    1,2-amino alcohol of formula

wherein R¹² represents a phenyl group optionally substituted by a Cl,Br, SO₂Me, F, SMe, OMe, NO₂ or C₁₋₄ alkyl group, R¹³ represents a C₁₋₄alkyl group, a R¹² group or a CH₂OSi(R¹³)₃ group and R¹⁴ represents abenzyl or C₁₋₄ alkyl, or the two R¹⁴ are bonded together to form a C₄₋₅heterocycle;

or a sodium, potassium or cesium salt of an optically active 1,2-iminoalcohol of formula

wherein each R¹² has the meaning indicated above; or

-   d) a sodium, potassium or cesium salt of an optically active alcohol    of formula

wherein each R¹² has the meaning indicated above.

Specific examples of the above mentioned optically active sodium,potassium or cesium alkoxides are a sodium, potassium or cesium salt ofany one of the compounds of formula 1 to 12:

the dotted line representing a single or double bond;said compounds having proved to be particularly useful for theinvention's process wherein the starting compound (I) is a macrocycle.

It is also useful to mention that the optically active alkoxide can becharacterized by a specific enantiomeric excess (e.e.). In general,optically active alkoxide having a higher e.e. provided compounds (I)with higher e.e. Therefore, it is preferable to employ in theinvention's process optically active alkoxide having e.e. of at least50% or even of at least 90%.

The optically active alkoxide can be added to the reaction medium in alarge range of concentration. As non-limiting examples, one can cite asoptically active alkoxide concentration values ranging from 0.2 to 20molar equivalents, relative to the di-ketone (I). Preferably, theoptically active alkoxide concentration will be comprised between 1.0and 8.0 molar equivalents. It goes without saying that the optimumconcentration of said alkoxide will depend on the nature of the latterand on the desired time of reaction.

The chiral sodium, potassium or cesium alkoxide can be in the form of apreformed salt or it can be formed in situ prior to its use, e.g. bypre-mixing a chiral compound comprising at least one moiety having ahydroxy group and an appropriate sodium, potassium or cesium base.

According to a particular embodiment of the invention the preferredalkoxides are the sodium or potassium alkoxides.

Furthermore, the process can be performed in the presence of anadditive. Said additive is a compound capable of reacting with or trapwater and is believed to favor the formation of the desired product.

Examples of useful additives are:

-   i) an alkaline or alkaline earth hydride, such as NaH, KH, CaH₂,    LiH;-   ii) a reaction-medium insoluble inorganic material capable to form a    chlatrate with water, such as an anhydrous zeolite, preferably of    the 4 Å type, or anhydrous NaOH, NaCl, Na₂CO₃, MgSO₄, Na₂SO₄, Na₂O,    CaCl₂ or MgCl₂; or-   iii) an organic material capable of reacting with water to form    non-acidic compounds, such as an ^(t)BuONa, orthoester,    N-methyl-N-trimethylsilyl-trifluoroacetamide or    1-trimethylsilylimidazole.

According to a further embodiment of the invention, preferred additivesare NaH, KH, anhydrous zeolite of the 4 Å type, ^(t)BuONa or anhydrousKOH, NaOH, NaCl, Na₂CO₃, Na₂SO₄.

The additive can be added to the reaction medium in a large range ofamounts which depend on the exact nature of the additive. However, theaddition of amounts which exceed three times the amount theoreticallyneeded to trap all the water which can theoretically be formed does notprovide any appreciable additional benefit.

The process of the invention can be carried out in the presence or inthe absence of solvent, but in any case it is advantageously performedunder anhydrous conditions, e.g. in the presence of less than 0.5% w/wof water. As a person skilled in the art can anticipate, the presence ofa solvent is mandatory only in the case in which the starting di-ketone(I) is a solid compound under the reaction conditions.

However, according to a preferred embodiment of the invention, andindependently of the physical state of the starting di-ketone (I), theprocess is advantageously carried out in the presence of a solvent. Saidsolvent must be chemically compatible with the reaction and does notdeactivate the alkoxide.

A suitable solvent is one which is aprotic. Non-limiting examples ofsuch a solvent are ethers, esters, amides, amines, aromatic solvents,linear or branched or cyclic hydrocarbons, chlorinated solvents andmixtures thereof. More preferably, the solvent is a C₄-C₆ ether such asTHF or dioxane, a C₃-C₆ amine such as NEt₃, pyridine, N-Me-pyrrolidineor N-Me-morpholine, C₃-C₆ amides such as DMF or N-Methyl pyrrolidone,methylene chloride, a C₆-C₁₀ aromatic solvent such as toluene oranisole, or mixtures thereof.

The temperature at which the process of the invention can be carried outis comprised between −20° C. and 100° C., preferably between 0° C. and60° C. Of course a person skilled in the art is also able to select thepreferred temperature as a function of the melting and boiling point ofthe starting and final products and/or an eventual solvent.

EXAMPLES

The invention will now be described in further detail by way of thefollowing example, wherein the abbreviations have the usual meaning inthe art, the temperatures are indicated in degrees centigrade (° C.);the NMR spectral data were recorded in CDCl₃ with a 360 MHz or 100 MHzmachine for ¹H or ¹³C respectively, the chemical displacements δ areindicated in ppm with respect to TMS as standard, the coupling constantsJ are expressed in Hz.

Example 1 Preparation of Optically Active14-methyl-bicyclo[9.4.0]pentadec-1(11)-en-12-one

a) General Procedure:

In the reaction vessel, under inert atmosphere, were introduced 126 mgof 3-methyl-1,5-cyclopentadecanedione, 3 ml of dry THF, optionally 200mg of anhydrous molecular sieve 4 Å or 2 molar equivalents of NaH, andthe Na-alkoxide or K-alkoxide 1-12, according to Table 1, dissolved intodry THF. The total amount of THF present was calculated in order to keepthe concentration of the starting dione between 0.1 and 0.4 mol/L at thebeginning of the reaction.

The reaction mixture was stirred at room temperature and followed by GC.To stop the reaction the mixture was hydrolyzed with water or an aqueous2N HCl solution. After extraction of the aqueous layer with diethylether the organic layer was dried over MgSO₄ and filtered. The solventwas removed under vacuum and the residue was purified either by flashchromatography or by bulb to bulb distillation to yield in the desiredproduct, i.e. (S)-14-methyl-bicyclo[9.4.0]pentadec-1(11)-en12one or(R)-14-methyl-bicyclo[9.4.0]pentadec-1(11)-en-12-one or an opticallyactive mixture of said stereoisomers depending on the configuration ofthe alkoxide.

¹H-NMR: 1.04(d, J=6.1 Hz, 3H), 1.18-1.46(m, 10H), 1.50-1.75(m, 4H),1.97-2.15(m, 3H), 2.30-2.40(m, 3H), 2.41-2.56(m, 3H).

¹³C-NMR: 21.3, 23.5, 24.6, 25.1, 25.3, 25.5, 26.0, 26.2, 26.6, 29.7,32.3, 38.3, 46.7, 136.3, 158.2, 199.7.

The results obtained are shown in Table 1.

TABLE 1 yields and e.e. of the final product as a function of thealkoxide used. Alkoxide¹⁾ M²⁾ Eq.³⁾ t⁴⁾ additive Yield⁵⁾ e.e⁶⁾ 1 Na 2 14NaH 99% 44% ee (R) 2 Na 2 3 NaH 93% 31% ee (R) 3 Na 2 2 NaH 80% 31% ee(R) 4 Na 1 6 NaH 35% 18% ee (S) 5 Na 1 6 NaH 23% 26% ee (S) 6 Na 4 3 MS*76% 39% ee (R) 7 Na 8 3 — 99% 74% ee (S) 7 K 4 1 MS* 99% 34% ee (S) 7 Cs4 46 MS* 75% 42% ee (S) 8 Na 4 3 MS* 69% 59% ee (S) 8 K 4 1.5 MS* 99%61% ee (S) 9 Na 4 14 NaH 25% 25% ee (S) 10 Na 4 4 NaH 80% 37% ee (S) 11Na 2 1 NaH 85% 28% ee (R) 12 Na 2 4 NaH 94% 37% ee (R) *MS is molecularsieve ¹⁾see description ²⁾metal of the alkoxide salt ³⁾number of molarequivalent of alkoxide introduced, relative to the starting dione⁴⁾duration of the reaction in day ⁵⁾determined by GC ⁶⁾determined byreacting the final product with an excess of LiAlH₄ in dry THF. Afterhydrolysis, filtration and extraction in Et₂O, the allyl alcoholobtained was analyzed by GC with a chiral column (CHIRASIL DEX CB) todetermine the enantiomeric excess of the resulting allyl alcohol.

1. A process for the preparation of a compound of formula

wherein the R¹ represents a linear C₇-C₉ alkanediyl or alkenediyl groupthat is optionally substituted; R² represents a C₁₋₆ linear, branched orcyclic alkyl or alkenyl group that is optionally substituted or a phenylgroup that is optionally substituted; and the asterisk means that saidcompound (II) is in an optically active form; by treating an achiraldi-ketone, the substrate, of formula

wherein R¹ and R² have the meaning indicated in formula (II), in thepresence of an optically active sodium, potassium or cesium alkoxide. 2.A process according to claim 1, wherein R² represents a C₁₋₆ linear,branched or cyclic alkyl group.
 3. A process according to claim 1,wherein the compound of formula (I) is3-methyl-1,5-cyclopentadecanedione, and the compound of formula (II) is(S)-14-methyl-bicyclo[9.4.0]pentadec-1(11)-en-12-one or(R)-14-methyl-bicyclo[9.4.0]pentadec-1(11)-en-12-one or an opticallyactive mixture of said stereoisomers.
 4. A process according to claim 1,wherein the optically active sodium, potassium or cesium alkoxide is anoptically active sodium, potassium or cesium salt of a C₄-C₄₀ compoundcomprising one, two or three of alkoxy groups or of a carbohydrate or ofa polymer comprising optically active alkoxy groups.
 5. A processaccording to claim 1, wherein the optically active sodium, potassium orcesium alkoxide is: a) a sodium, potassium or cesium salt of a C₄-C₁₈optically active mono alcohol; b) a sodium, potassium or cesium salt ofa C₃-C₁₈ optically active 1,2-diol, a C₄-C₁₈ optically active 1,3-diol,a C₅-C₃₅ optically active 1,4-diol; c) a sodium, potassium or cesiumsalt of a C₄-C₂₅ optically active alcohol containing a nitrogen in the βposition; d) a sodium, potassium or cesium salt of a C₁₅₋₃₈ compoundhaving two or three groups derived from an optically active alkoxidementioned under a), b) or c); or e) a sodium, potassium or cesium saltof an optically active alkoxide, mentioned under d) and which issupported on an insoluble material.
 6. A process according to claim 1,wherein the optically active sodium, potassium or cesium alkoxide is: a)a sodium, potassium or cesium salt of an optically active alcohol offormula

wherein R³ represents a C₁₋₄ alkyl group or an optionally substitutedphenyl group and R⁴ represents a C₁₋₄ alkyl group or a C(R⁵)₂(OR^(4′))group, R⁵ representing a hydrogen atom or a R³ group and R^(4′)representing a C₁₋₆ alkyl group, an optionally substituted phenyl orbenzyl group or a C₃₋₉ trialkyl silyl or a triphenyl silyl group; or achiral alcohol of formula R^(3′)—OH, wherein R^(3′) represents a C₇₋₁₂chiral hydrocarbon group; b) a sodium, potassium or cesium salt of anoptically active diol of formula

wherein R⁶ represents an optionally substituted phenyl group, a C₁₋₆alkyl group or a COOR⁷ group, R⁷ representing a C₁₋₄ alkyl group; asodium, potassium or cesium salt of an optically active diol of formula

wherein each R⁶ has the meaning indicated above; a sodium, potassium orcesium salt of an optically active diol containing a moiety of formula

a sodium, potassium or cesium salt of an optically active diol offormula

wherein R⁵ has the meaning indicated above; c) a sodium, potassium orcesium salt of an optically active 1 ,2-amino-alcohol of formula

wherein R³ has the meaning indicated above, R^(7′) represents a R⁴ or R⁵group as defined above and R⁸ represents an optionally substitutedphenyl group or a C₁₋₉ alkyl or alkylbenzene group and R^(8′) representsa R⁸ group or a SO₂R³, R³CO, CH₂CH₂NR³ ₂, SiR³ ₃, PO(OR³)₂ group;optionally R³ and R^(7′) can be bonded together to form a C₅₋₁₀ ring orR^(7′) and R⁸ can be bonded together to form a C₄₋₅ heterocycle, or R⁸and R^(8′) can be bonded together to form a C₂₋₅ heterocycle; or asodium, potassium or cesium salt of an optically active iminoalcohol offormula

wherein each R³, R⁵ and R^(7′) have the meaning indicated above; d) asodium, potassium or cesium salt of an optically active C₁₅₋₃₈ compoundhaving two or three groups derived from an optically active alkoxidementioned under a), b) or c); or e) a sodium, potassium or cesium saltof an optically active compound mentioned under d) and which issupported on silica, a Merrifield resin, gold or a polystyrene.
 7. Aprocess according to claim 1, wherein the optically active sodium,potassium or cesium alkoxide is: a) a sodium, potassium or cesium saltof an optically active alcohol of formula

wherein R⁹ represents a C₁₋₄ alkyl group or an optionally substitutedphenyl or benzyl group and R¹⁰ represents a phenyl group optionallysubstituted by one C₁₋₄ alkyl group; b) a sodium, potassium or cesiumsalt of an optically active 1,2-diol of formula

wherein each R¹⁰ has the meaning indicated above; or a sodium, potassiumor cesium salt of an optically active 1,4-diol of formula

wherein each R¹¹ represents a C₁₋₄ group or a hydrogen atom; c) asodium, potassium or cesium salt of an optically active 1,2-aminoalcohol of formula

wherein R¹² represents a phenyl group optionally substituted by a Cl,Br, SO₂Me, F, SMe, OMe, NO₂ or C₁₋₄ alkyl group, R¹³ represents a C₁₋₄alkyl group, a R¹² group or a CH₂OSi(R¹³)₃ group and R¹⁴ represents abenzyl or C₁₋₄ alkyl, or the two R¹⁴ are bonded together to form a C₄₋₅heterocycle; or a sodium, potassium or cesium salt of an opticallyactive 1,2-imino alcohol of formula

wherein each R¹² has the meaning indicated above; or d) a sodium,potassium or cesium salt of an optically active alcohol of formula

wherein each R¹² has the meaning indicated above.
 8. A process accordingto claim 1, wherein the optically active sodium, potassium or cesiumalkoxide is a sodium, potassium or cesium salt of any one of thecompounds of formula 1 to 12:

the dotted line representing a single or double bond.
 9. A processaccording to claim 1, wherein the optically active alkoxide has an e.e.of at least 90%.
 10. A process according to claim 1, wherein theoptically active alkoxide is a sodium or potassium optically activealkoxide.
 11. A process according to claim 1, wherein said process iscarried out in the presence of an additive selected from the groupconsisting of i) an alkaline or alkaline earth hydride; ii) areaction-medium insoluble inorganic material capable to form a chlatratewith water; and iii) an organic material capable of reacting with waterto form non-acidic compounds.
 12. A process according to claim 11,wherein the additive is selected from the group consisting of NaH, KH,anhydrous zeolite of the 4 Å type, ^(t)BuONa or anhydrous KOH, NaOH,NaCl, Na₂CO₃, Na₂SO₄.
 13. A process according to claim 1, wherein theprocess is carried out in the presence of a solvent and said solvent isselected from the group consisting of a C₄-C₆ ether, a C₃-C₆ amine, aC₃-C₆ amides, methylene chloride, a C₆-C₁₀ aromatic solvent and mixturesthereof.